Mission Statement

As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.”

Pediatric, Developmental and Genetic Ophthalmology

Current Research

The Pediatric, Developmental and Genetic Ophthalmology Section, headed by Brian P. Brooks, MD, PhD., seeks to understand the genetic, molecular and developmental basic of inherited eye diseases that affect children and to evaluate novel approaches to therapy for these conditions. The two main areas of research at present are: 1) the genetics of uveal coloboma and 2) treatments for oculocutaneous albinism.

UVEAL COLOBOMA

Uveal coloboma is a potentially blinding, developmental abnormality of the eye caused by failure of the optic fissure to close during the 5th week of human gestation. The purpose of our clinical and basic research is to better understand the genetic and developmental mechanisms of optic fissure closure. Our short-term goal is to provide better diagnostics and genetic counseling for our patients; our long-term goal is to find preventions and/or treatments for this condition. Our approach is summarized in the following figure:

Our clinical studies are focused on understanding the coloboma phenotype more deeply (https://clinicaltrials.gov/ct2/show/NCT01778543?term=coloboma&rank=2), including deep ocular and systemic phenotyping, where appropriate, leveraging the unparalleled resources of the NIH Clinical Center. Genetic analysis using the tools of whole exome/whole genome sequencing are being undertaken to identify causative genes and improve genetic counselingpatients with coloboma see and what, if any, associated clinical conditions they might have.

A complementary approach to understanding genes important in optic fissure closure in humans is the laboratory use of animal models. We use mouse and zebrafish models to better understand how genes are regulated during the course of optic fissure closure. Specific mutant mouse strains are also being investigated to discover genes that might cause coloboma in humans. These studies have identified that two zinc finger proteins, Nlz1 and Nlz2, regulate optic fissure closure, perhaps through a Pax2-dependent mechanism. We are currently trying to understand the developmental role of these and other genes from our screen in the normal process of optic fissure closure and to search for causative mutations in humans.

ALBINISM

Oculocutaneous albinism (OCA) is an inherited disease characterized by reduced melanin pigment in the hair, skin and eyes. Patients with OCA have reduced best-corrected visual acuity, likely due to developmental eye defects such as foveal hypoplasia and abnormal routing of ganglion cell axons at the level of the optic chiasm. The precise reason why changes in melanin pigmentation during development result in developmental eye abnormalities is unclear. However, we hypothesize that improving the process of melanin production may secondarily improve the visual potential of patients with albinism, if given during an appropriate developmental window.

To this end, we are trying to identify compounds that might improve melanin pigmentation in laboratory models and, therefore, be candidates for pilot clinical trials. For example, we have found that treatment of a mouse model of one form of albinism, OCA1b, with an FDA-approved drug, nitisinone, improves eye and fur pigmentation. We are conducting a pilot, proof-of-concept clinical trial of this drug in five adults with OCA1b. We are also evaluating whether nitisinone improves melanin pigmentation in mouse models of other forms of albinism. Lastly, in collaboration with the National Center for Advanced Therapeutics (NCATS), we are screening pharmaceutical libraries for compounds that may activate the rate-limiting enzyme in melanin synthesis, tyrosinase.